Total Synthesis of (±)-Welwitindolinone A Isonitrile

A highly stereoselective total synthesis of the alkaloid natural product welwitindolinone A isonitrile has been completed. The synthesis utilizes a chloronium ion mediated semi-pinacol rearrangement to simultaneously install the C10 quaternary center and neopentyl chlorine and a novel anionic cyclization to construct the spiro-oxindole with complete stereocontrol

Evolution of a Synthetic Strategy: Total Synthesis of (±)-Welwitindolinone A Isonitrile

An efficient and highly stereoselective total synthesis of the natural product (±)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI_2−LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties

Syntheses, crystal and solution structures, ligand exchange, and ligand coupling reactions of mixed pentaarylantimony compounds

All the possible combinations of mixed pentaarylantimony compounds bearing p-methylphenyl and p-trifluoromethylphenyl groups were synthesized, i.e., ArnTol5-nSb (n = 0-5: Ar = p-CF3C6H4, Tol = p-CH3C6H4): Tol5Sb (1), ArTol4Sb (2), Ar2Tol3Sb (3), Ar3Tol2Sb (4), Ar4TolSb (5), and Ar5Sb (6). Compounds 2-5 are the first well-characterized examples of mixed acyclic pentaarylantimony species. The structures of 2-6 were determined by X-ray crystallography to bear trigonal bipyramidal (TBP) geometry with the more electronegative p-trifluoromethylphenyl substituents selectively occupying the apical positions. Considerations based upon the chemical shifts of the ipso carbons of the aryl and the tolyl groups suggested that the solution structures of 1-6 were also TBP although pseudorotation of them could not be frozen even at –80 °C. Ligand exchange reactions (LERs) were found to take place between 1 and 6 at ca. 60 °C in [D6]benzene and all the six species 1-6 were found in the equilibrium mixture. The relative stabilities of 1-6 were determined quantitatively by comparison of the observed molar ratios of 1-6 in equilibrium with calculated statistical molar ratios, and Ar2Tol3Sb (3) was found to be the most stable. The ligand coupling reactions (LCRs) from 2-5 in solution were found to be greatly accelerated by adding Cu(acac)2 or Li+TFPB– [TFPB: B(3,5-(CF3)2C6H3)4], with the rate becoming comparable with the LER. The use of flash vacuum thermolysis (FVT) allowed the LCR to occur with very little ligand exchange except in the case of ArTol4Sb where it was very fast. The selectivities of LCRs determined by the yield of the formed biaryls by FVT were highly consistent with those in the catalyzed reactions in solution, where bitolyl was not obtained at all. The experimental results suggested that the LCR of pentaarylantimony compounds proceeds in the manner of apical-apical coupling

Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1<i>H</i>-pyrrol-3-yl]-<i>N</i>-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log <i>D</i> and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound <b>13e</b> exhibited potent H⁺,K⁺-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound <b>13e</b> (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1<i>H</i>-pyrrol-3-yl]-<i>N</i>-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases